Complement in Allergic Lung Disease

描述(由申请人提供)：这项研究提案的目的是描述补体在过敏性肺部疾病发病机制中的整体作用和潜在机制。这项建议的具体目标是由一个中心假设驱动的，即补体激活产物调节过敏原诱导的呼吸道疾病的关键特征，包括气道高反应性(AHR)和急性呼吸道炎症。这一建议的结果将有助于评估补体作为治疗哮喘的可能靶点。过敏原诱导的特定补体缺乏的小鼠肺过敏模型将被用来确定补体途径、激活片段和受体，这些可能在过敏性肺部疾病的发病机制中起重要作用。接受该模型的补体缺乏动物将被检查是否减轻哮喘的病理和生理特征，包括AHR、呼吸道粘液高分泌、IgE水平升高和肺嗜酸性粒细胞。被认为在哮喘中起关键作用的Th2细胞因子(IL-4、IL-5、IL-13)也将被检测其表达的变化。除了小鼠实验性过敏模型外，还将使用人类T细胞以及从过敏性肺病患者中分离的其他白细胞进行研究，以检查哮喘患者补体介导的细胞反应可能发生的变化。为了实现这一研究目标，提出了四个特定的目标：1)在过敏原诱导的肺过敏模型中，检测每个补体激活途径在诱发哮喘相关反应中的重要性；2)确定补体过敏毒素受体(C3aR和C5aR)如何在过敏原诱导的肺过敏模型中影响哮喘相关反应；3)在过敏原诱导的小鼠肺过敏模型中，确定补体第五成分(C5)如何影响哮喘相关反应；以及4)确定补体过敏毒素(C3a和C5a)在调节哮喘中T细胞介导的反应中的生物学作用。

DESCRIPTION (provided by applicant): The objective of this research proposal is to delineate the overall contribution and potential mechanisms that complement utilizes to mediate the pathogenesis of allergic lung disease. The specific aims of this proposal are driven by the central hypothesis that complement activation products regulate key features of allergen-induced airway disease, including airway hyperresponsiveness (AHR) and acute airway inflammation. The results of this proposal will facilitate the evaluation of complement as a possible therapeutic target in the treatment of asthma. An allergen-induced model of pulmonary allergy in mice with specific complement deficiencies will be used to identify the complement pathways, activation fragments, and receptors that are potentially important in mediating the pathogenesis of allergic lung disease. The complement-deficient animals that are subjected to the model will be examined for attenuation of pathological and physiological hallmarks of asthma, including AHR, airway mucus hypersecretion, elevated IgE levels and lung eosinophils. The Th2 cytokines (IL-4, IL-5, IL-13) that have been proposed to play a pivotal role in asthma will also be examined for altered expression. In addition to the murine experimental allergic model, studies with human T-cells as well as other leukocytes isolated from patients with allergic lung disease will be used to examine potentially altered complement mediated cellular responses in asthma. Four specific aims are proposed to accomplish the research goals: 1) to examine the importance of each complement activation pathway in eliciting the asthma associated responses in an allergen-induced model of pulmonary allergy, 2) to determine how the complement anaphylatoxin receptors (C3aR and C5aR) affect the asthma associated responses in an allergen-induced model of pulmonary allergy, 3) to determine how the fifth complement component (C5) affects the asthma associated responses in an allergen-induced mouse model of pulmonary allergy, and 4) to determine the biological effects of the complement anaphylatoxins (C3a and C5a) in regulating T-cell mediated responses in asthma.